Drug discovery research involves the screening of large numbers of chemical compounds before a drug candidate is identified. One factor limiting the success of this process is the ability to rapidly synthesize compounds for testing in various screening assays. Recent advances in high through-put screening have increased the need for improved methods for rapid synthesis of compounds for testing.
Methods for solid phase synthesis of peptides have been used for many years to rapidly prepare peptides of various size and composition. Application of this technology to non-oligomeric small organic molecules could provide a method for rapid synthesis of large numbers of compounds. However, because such small organic molecules are not oligomeric and they frequently do not contain functional groups which lend themselves to coupling to solid phase supports, solid phase synthetic methods are not readily applicable.
HIV protease inhibitors are known to be useful for inhibiting HIV protease and for inhibiting an HIV infection in humans. The HIV protease inhibitors are an example of a class of compounds for which it is not obvious how solid phase synthetic methods can be readily applied.
In particular, the classes of HIV protease inhibitors represented by A77003 and A80987, and the like, present challenges for solid phase synthetic methods because (1) these molecules do not contain a functional group (typically, a carboxyl group) which can be used to attach the molecule to a solid support and (2) these molecules extend in both directions from the central diamino diol or diamino alcohol core unit, which is contradictory to the conventional unidirectional solid phase synthesis methods used to prepare peptides. ##STR1##
The HIV protease inhibitors A77003 and A80987 are disclosed in U.S. Pat. No. 5,142,056, issued Aug. 25, 1992 and U.S. Pat. No. 5,354,866, issued Oct. 11, 1994, respectively, both of which are incorporated herein by reference.
It has now been discovered that HIV protease inhibitors of the types represented by A77003 and A80987 can be readily synthesized using solid phase methods.